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Can paternal preconceptional radiation account for the increase of leukaemia and non-Hodgkin's lymphoma in Seascale?

OBJECTIVE: To determine if the excess of leukaemia and non-Hodgkin's lymphoma in Seascale is restricted to those born in the parish and whether it might be explained by the postulated relation with paternal preconceptional radiation. DESIGN: Comparison, separately for those born in the parish and those born elsewhere, of the numbers of these malignancies observed in Seascale with those expected on the basis of reference rates for England and Wales. Details of paternal radiation levels were sought for each case. SETTING: The parish of Seascale in west Cumbria. SUBJECTS: Residents of Seascale below age 25 years in the years 1951-91. MAIN OUTCOME MEASURES: The observed and expected numbers of cases of leukaemia and non-Hodgkin's lymphoma within Seascale among those born there and among those born elsewhere. Also, the levels of any paternal preconceptional radiation associated with each case. RESULTS: A significant excess of leukaemia and non-Hodgkin's lymphoma at ages 0-24 was found in Seascale in those who were born there (ratio of observed to expected cases 8.6 and 20.2 respectively; p < 0.01). This also applied to those not born there (7.2 and 16.5; p < 0.01), a group often regarded as not showing an excess. The estimates were then conservatively recalculated so as to overestimate the risks among those born in Seascale and underestimate them among those born elsewhere. On this basis the six cases in those born in Seascale compare with 0.38 expected (15.8; p < 0.001), of which two were associated with paternal preconceptional life-time levels of 100 mSv or greater and three others with levels of 90-99 mSv. Among those born elsewhere, there were five cases (expected 0.74; ratio 6.7, p < 0.01), of which only one was associated with a high level of such radiation. CONCLUSIONS: Paternal preconceptional radiation cannot be the sole cause of the excess in Seascale since it will not explain the excess among those born outside Seascale. It follows that, unless two causes are to be postulated, any single cause must be a factor other than paternal preconceptional radiation. On this basis, the association found among those born there, if not partly due to chance, may reflect an indirect relation with the true cause. The recent hypothesis about such paternal radiation has originated in a subgroup of the excess cases that have aroused concern.

Adolescent↗

Maternal and paternal genomes function independently in mouse ova in establishing expression of the imprinted genes Snrpn and Igf2r: no evidence for allelic trans-sensing and counting mechanisms.

It has often been suggested that the parental-specific expression of mammalian imprinted genes might be dependent on maternal-paternal intergenomic or interallelic interactions. Using quantitative allele-specific RT-PCR single nucleotide primer extension assays developed for two imprinted genes, Snrpn and Igf2r, we demonstrate: (i) No role for maternal-paternal allelic interactions: the modes of parental-specific expression of Snrpn and Igf2r in normal ova were unchanged in gynogenetic and androgenetic ova; the latter contain two maternal and two paternal genomes respectively, and cannot undergo maternal-paternal interactions. (ii) No role for allelic counting or exclusion mechanisms: in individual blastomeres of androgenetic ova, both paternal Snrpn alleles were active (Snrpn was not expressed in gynogenetic ova), and in individual gynogenetic and androgenetic blastomeres, both maternal and paternal Igf2r alleles, respectively, were active. (iii) No role for ploidy: the mode of parental-specific expression of Snrpn and Igf2r in normal diploid ova was unchanged in individual blastomeres of triploid and tetraploid ova. Thus, the maternal and paternal genomes function independently in establishing the pre-implantation mode of parental-specific expression of Snrpn and Igf2r, with no role for trans-allelic/genomic interaction phenomena. In addition, the results show that inactive and biallelic modes of expression of imprinted genes are potential mechanisms for the death of gynogenones and androgenones at the peri-implantation stage.

Alleles↗

The justification of medical paternalism.

This paper examines the moral justification of medical paternalism. It is shown that while there are sufficient grounds to justify the practice of medical paternalism in some instances, there are many instances of the practice which cannot be justified. The application of the utilization principle of paternalism is considered in detail. It is argued that the physician can justifiably apply the principle in a particular case only after he has determined both that there are no alternate non-paternalistic courses of action which will have the same results and that he is in the same privileged position with respect to any relevant non-medical considerations as he is in with respect to medical considerations. The moral constraints on paternalistic action flowing from the concept of personal autonomy are also examined. It is concluded that medical paternalism is justified only when utilitarian considerations apply and when they do not violate personal rights. This occurs only when the subject of paternalism is not fully competent, when he has explicitly or by implication given consent, or when it can be reasonably concluded, from the knowledge of his emotional and cognitive make up, that he would approve of such treatment. For the most part, only the physician with a more intimate knowledge of his patient than is possible in most modern medical practice is in the position to undertake medical paternalism with moral propriety.

Attitude↗

Effect of paternal age in achondroplasia, thanatophoric dysplasia, and osteogenesis imperfecta.

The paternal ages of nonfamilial cases of achondroplasia (AC) (n = 78), thanatophoric dysplasia (TD) (n = 64), and osteogenesis imperfecta (OI) (n = 106), were compared with those of matched controls, from an Italian Indagine Policentrica Italiana sulle Malformazioni Congenite and a South American Estudio Colaborativo Latinoamericano de Malformaciones Congénitas series. The degree of paternal age effect on the origin of these dominant mutations differed among the three conditions. Mean paternal age was highly elevated in AC, 36.30 +/- 6.74 years in the IPIMC, and 37.19 +/- 10.53 years in the ECLAMC; less consistently elevated in TD, 33.60 +/- 7.08 years in the IPIMC, and 36.41 +/- 9.38 years in the ECLAMC; and only slightly elevated in OI in the ECLAMC, 31.15 +/- 9.25 years, but not in the IPIMC, 32.26 +/- 6.07 years. Increased maternal age or birth order in these conditions disappeared when corrected for paternal age. Approximately 50% of AC and TD cases, and only 30% of OI cases, were born to fathers above age 35 years. For AC and TD, the increase in relative incidence with paternal age fitted an exponential curve. The variability of paternal age effect in these new mutations could be due, among other reasons, to the high proportion of germ-line mosaicism in OI parents, or to the localization of the AC gene, mapped to the 4p16.3 region, in the neighborhood of an unstable DNA area.

Achondroplasia↗

Effect of paternal tamoxifen on the expression of insulin-like growth factor 2 and insulin-like growth factor type 1 receptor in the post-implantation rat embryos.

Nuclear transplantation studies demonstrated the importance of paternal contribution to embryogenesis. Paternal treatment with agents like cyclophosphamide and 5-azacytidine has been shown to cause an increase in pre-implantation loss (PIL) and post-implantation loss (POL). Studies from our laboratory have shown that paternal tamoxifen treatment increases PIL and POL. It was observed that the PIL occurred at day 2 of gestation (embryo at 2-4 cell stage) and the POL occurred around day 9 of gestation (mid-gestation). The insulin-like growth factor (IGF) system represents one of the major growth-controlling system expressed in the embryo. Several studies suggest that in rodents, insulin-like growth factor 2 (Igf2) signaling through the insulin-like growth factor type 1 receptor (Igf1r) modulates embryo growth at around days 9-11 of gestation (mid-gestation). The present study was undertaken to evaluate the expression of Igf2 and Igf1r transcript by RT-PCR in the post-implantation embryos obtained after paternal tamoxifen treatment. It was observed that both the genes were down regulated in resorbed embryos (POL). Since Igf2 is an imprinted gene and the imprint mark is established during spermatogenesis, the present study suggests that paternal tamoxifen treatment may have affected imprinting of the gene during spermatogenesis thereby decreasing its expression and leading to increase in POL. This is to our knowledge the first study correlating the increase in post-implantation embryo loss obtained after paternal drug treatment with the decrease in the expression of Igf2 in these embryos.

Animals↗

Paternal hamsters mechanically assist the delivery, consume amniotic fluid and placenta, remove fetal membranes, and provide parental care during the birth process.

We report the first description of a male mammal behaviorally participating in the birth of his young. Djungarian hamsters, Phodopus campbelli, are naturally biparental and males contribute to pup survival and growth through direct paternal care and indirect effects on maternal physiology. Males of the closely related Siberian hamster, P. sungorus, have only seasonal opportunities to interact with pups and neither contribute to pup survival and growth nor provide extensive paternal care under laboratory conditions. Male P. campbelli undergo a series of hormonal changes prior to the birth of their first litter which are not shared with P. sungorus males and may "prime" males to express paternal behavior. We hypothesized that P. campbelli males would behave paternally on first contact with pups during the birth process, whereas P. sungorus males would not. In addition to showing paternal behavior toward neonates, male P. campbelli licked amniotic fluid before the birth, mechanically assisted the delivery, opened an airway by clearing the nostrils (so that pups flushed red with oxygenation), licked and sniffed pups in the moments and minutes after birth to clean the pups of membranes, and ate the placenta. None of these behaviors were observed in P. sungorus. We anticipate that P. campbelli will not be the only species with highly developed paternal behavioral repertoires during the birth.

Amnion↗

Mathematical aspects of the paternity index I = X/Y, especially in relation to the chance of non-exclusion of non-fathers.

In a previous paper the author mentioned some aspects of the paternity index I (= X/Y): Among false triplets the frequency of those with I equal to or higher than an (observed) I value of Ix is considerably lower than 1/Ix; among false triplets the mean value of I is equal to 1, and among non-excluded non-fathers it is equal to the inverse of the chance of non-exclusion; among true triplets the mean value of 1/I (= i) is equal to the chance of non-exclusion of non-fathers. In a statistical material rather strong deviations from some of these expectations were observed. In the present paper further characteristics of the distribution of I values were taken into consideration, and especially those that should hold if lnI would fit in with a normal distribution. It was supposed that with the aid of such a distribution the deviations mentioned above could be recognized as chance variability. It appears, however, that neither the logarithms of the paternity index, nor those of the zygosity index of twins (chosen as an analogous model that is more easily analysable than the paternity index) are really normally distributed. This, in turn, makes that estimates of probability of paternity, based on such a supposition, are of doubtful reliability. Besides it is concluded that also for other reasons other estimates than Essen-Möller's W (or I or i), as probability of first type errors, lead in practice to conclusions that are equally subdue to a priori suppositions as are W values and may be, in fact, much more erroneous than those. Special attention is paid to the statistical analysis of paternity studies with more than one alleged father, and it is concluded that in such cases the general formula that may be considered to be equivalent with Essen-Möller's formula for one-man paternity cases, i.e., W = X/(X + Y) or I/(I + 1), must be W1 = I1/(sigma I + n); W2 = I2/(sigma I + n) etc. and certainly not W1 = I1/(sigma I + 1); W2 = I2/(sigma + 1) etc.

Adult↗

Investigation of paternity establishing without the putative father using hypervariable DNA probes.

Seven kinds of DNA probes which recognize hypervariable loci were applied for paternity test. The putative father was decreased and unavailable for the test. The two legitimate children and their mother (the deceased's wife) and the four illegitimate children and their mother (the deceased's kept mistress) were available for analysis. Paternity index of four illegitimate child was investigated. Allelic frequencies and their confidence intervals among unrelated Japanese individuals were previously reported from our laboratory, and co-dominant segregation of the polymorphism was confirmed in family studies. Cumulative paternity indices of four illegitimate children from 16 kinds of standard blood group markers were 165, 42, 0.09, and 36, respectively. On the other hand, cumulative paternity indices from 7 kinds of DNA probes are 2,363, 4,685, 57,678, and 54,994, respectively, which are 14, 113, 640, 864, and 1,509 times higher than that from standard blood group markers. The DNA analyses gave nearly conclusive evidence that the putative father was the biological father of the children. Especially, the paternity relation of the third illegitimate child could not be established without the DNA analyses. Accordingly, DNA polymorphism is considered to be informative enough for paternity test.

DNA↗

DNA microsatellites in domesticated dogs: application in paternity disputes.

Microsatellite sequences, like minisatellites, are a class of polymorphic DNA fragments that are randomly distributed throughout mammalian genome. Although they express significantly lower variation than minisatellites, they have potential to be used in paternity disputes. However, the inherently lower variability together with the more genetically homogeneous nature of pedigree dogs due to the major inbreeding, raised doubts about the effectiveness of microsatellites in canine paternity (paternage) testing. Using about 20 polymorphic canine specific microsatellites on various dog litters demonstrated, that canine microsatellites provide a perfectly adequate basis for assigning paternity in pedigree breeds. Microsatellite paternity tests are more straightforward to perform and interpret than those based on minisatellites (DNA fingerprinting) and require as little as 0.1 ml of blood. The case presented here was a paternity dispute in labradors, where a mixed paternity was suspected.

Alleles↗

The problem of single parent/child paternity analysis--practical results involving 336 children and 348 unrelated men.

In a certain amount of paternity investigations, only DNA from child and alleged father is analyzed, thus increasing the possibility of false paternity inclusions. The aim of this study was to determine how many wrong paternity inclusions could be detected in a rather small geographical area comparing empirical results from 336 children and 348 men (13-15 STRs were investigated per person). This comparison between each child and all unrelated men (i.e. all putative fathers from the other cases) with an especially designed computer program resulted in 116,004 man/child pairs. Less than three excluding STRs were found in 1666 child/unrelated man pairs (1.44% of the comparisons). At least one unrelated man with only two or less STR mismatches could be determined for 322 children (95.8% of all investigated children). In 26 comparisons no STR mismatches between a child and an unrelated man were detected, thus at least one and up to three "second father(s)" under 350 men could be found for 23 children, if the mother is excluded. Paternity probabilities between 95.475% and 99.996% were calculated. Our results underline the difficulties in motherless paternity cases using only STR analysis and advise great precaution in assigning verbal predicates such as "paternity proven" in those investigations.

Adult↗

Neither reduced photoperiod, nor female-related social cues, nor increased maternal thermal stress result in a paternally responsive Phodopus sungorus male.

Neither reduced photoperiod, nor female-related social cues, nor increased maternal thermal stress result in a paternally responsive Phodopus sungorus male. Physiol Behav [Volume # (Issue #)] 000-000, 2006. -Under laboratory conditions, P. sungorus males are not needed for pup survival and growth and are unresponsive to an experimentally displaced pup. However, males have been found with young pups late in the breeding season, and other laboratories have found evidence for biparental care. Thus, paternal behavior might be expressed in response to relevant social and environmental cues. Reduced photoperiod (from 14L:10D to 12L:12D), increased ambient temperature (from 18 to 23 degrees C) and pairing with an obligate biparental heterospecific female (to remove behavioral barriers to pup contact) were tested. Although within-animal responsiveness during a standardized pup displacement increased under reduced photoperiod, and pup retrieval occurred more often in the heterospecific pairing, paternal responsiveness scores remained negative, and typical of the species, rather than positive, and indicative of paternal responsiveness. Thus, P. sungorus males did not meet criteria for paternal responsiveness in terms of nest attendance, retrieval rates, or positive paternal responsiveness scores. Pup survival and development were not affected. In spite of their seasonal proximity to pups, there is no evidence that these environmental cues and manipulations are sufficient to result in biparental care.

Animals↗

The appropriate upper age limit for semen donors: a review of the genetic effects of paternal age.

There is little evidence to support a correlation between increased paternal age and the incidence of chromosome anomalies. Though a few early studies demonstrated an increased risk of Down syndrome with advanced paternal age, especially after the age of 55, numerous later studies failed to confirm any paternal age effect. Among structural chromosome anomalies, only the inherited reciprocal translocations were found to be more common among children of older fathers. Chromosome analysis of semen donors would rule out this problem. There is evidence, however, that the incidence of serious nonchromosomal birth defects, especially those arising from new autosomal mutations, increases with paternal age. Risk estimates have been established for increased paternal age and contribution to new dominant mutations. The established association between increased paternal age and new autosomal mutations and the fact that most of the disorders associated with such mutations cannot be prenatally diagnosed may be important in establishing the upper age limit for semen donors. Recommendations from the literature are interpreted to advise men to have their children before age 40. This suggestion would obviously benefit immediate offspring and perhaps successive generations as well. The limit of 35 years set by AATB standards, therefore, is in harmony with such benefit, but may be too stringent in eliminating potential donors. Accordingly, the Reproductive Council of the AATB has initiated steps to modify its standards to the age limit of 40.

Chromosome Aberrations↗

Paternal behavior is associated with central neurohormone receptor binding patterns in meadow voles (Microtus pennsylvanicus).

Paternal and nonpaternal voles (microtus) have different arginine-vasopressin (AVP) and oxytocin (OT) receptor patterns in the extended amygdala, a neural pathway associated with parental behavior. Using receptor autoradiography, the authors examined whether AVP and OT receptor patterns were associated with facultative paternal behavior in either sexually and parentally inexperienced or experienced meadow voles (Microtus pennsylvanicus). Experienced, in contrast to inexperienced, males had less AVP binding in the lateral septum (LS), more AVP binding in the anterior olfactory nucleus (AON), and more OT binding in the AON, bed nucleus of the stria terminalis, LS, and lateral amygdala. Thus, specific AVP receptor patterns, which co-occur with paternal care in consistently paternal voles, also may be associated with paternal care (when present) in typically nonpaternal species. This study also demonstrated a possible relationship between OT receptor patterns and paternal state in male mammals.

Amygdala↗

Multiple paternity and female-biased mutation at a microsatellite locus in the olive ridley sea turtle (Lepidochelys olivacea).

Multiple paternity in the olive ridley sea turtle (Lepidochelys olivacea) population nesting in Suriname was demonstrated using two microsatellite loci, viz., Ei8 and Cm84. The large number of offspring sampled per clutch (70 on average, ranging from 15 to 103) and the number of alleles found at the two loci (18 and eight alleles, respectively) enabled unambiguous assessment of the occurrence of multiple paternity. In two out of 10 clutches analysed, the offspring had been sired by at least two males, which was confirmed at both loci. In both clutches, unequal paternity occurred: 73% and 92% of the offspring had been sired by the primary male. The probability of detecting multiple paternity was 0.903, and therefore there is a small chance that multiple paternity occurred but remained undetected in some of the eight clutches that appeared to be singly sired. Analysis of 703 offspring revealed a high mutation rate for locus Ei8 (micro = 2.3 x 10(-2)) with all 33 mutations occurring in maternal alleles. In particular, one allele of 274 bp mutated at a high frequency in a clutch to which the mother contributed the allele, but in another clutch where the father contributed the same allele, no such mutations were observed. Inferred allele-specific mutation rates for Ei8 and expected numbers of mutations per clutch confirmed that maternal alleles for Ei8 are more likely to mutate in the olive ridley sea turtle than paternal alleles. Possible explanations are discussed.

Alleles↗

Characteristics of a DNA probe (pa3'HVR) when used for paternity testing.

DNA probes that detect polymorphic loci in the human genome are finding widespread application in many areas of genetic testing. Paternity testing represents one area for the application of probe technology; this report presents data obtained in a paternity testing program with a probe (pa3'HVR) derived from a locus (D16S85) approximately 8 kilobases (kb) downstream from the alpha globin gene complex on chromosome 16. The pa3'HVR probe used under stringent conditions of hybridization detects a highly polymorphic locus in chromosomal DNA digested with Pvu 2 restriction endonuclease. Alleles at the D16S85 locus were grouped into 58 size bins differing from one another by 100 base pairs in the black and white populations. The most common alleles detected in whites fell into the 2.3-kb group with a collective frequency of 0.1849. In blacks, the most common allele group is 2.0 kb with a collective frequency of 0.1333. The probe was used for restriction fragment length polymorphism mapping in conjunction with standard paternity testing techniques in 100 paternity cases. Thirty direct exclusions were encountered in the 100 cases with standard testing methods, versus 27 exclusions with the pa3'HVR probe alone. Four exclusions detected with standard methods were not detected with the probe and one exclusion detected with the probe was missed by standard testing. The probability of excluding a falsely accused man by use of the pa3'HVR probe was approximately 90 percent. In cases where exclusions were not encountered, the data obtained with the pa3'HVR probe increased the paternity index calculated from standard testing by about 16-fold.2+ informative for paternity testing.

Alleles↗

The value of variable number of tandem-repeat polymorphisms in cases of disputed paternity not resolved by conventional markers: two case reports.

Disputed paternity cases are routinely tested in the authors' laboratory for red cell antigen, plasma protein, red cell enzyme, and HLA polymorphisms. This report concerns two cases in which the above test results made exclusion of paternity doubtful. In one case, exclusion of paternity was based on one discrepancy in the Duffy blood group system only, a unique situation in the investigators' experience of more than 2500 cases; the investigators were, therefore, reluctant to use this as the only evidence of exclusion. In the other case, it was necessary to postulate the presence of a rare haplotype, MSu, in the MNS blood group system to explain paternity. It was therefore decided to investigate allelic variable number of tandem-repeat (VNTR) DNA polymorphisms in these disputed paternity trios. VNTR DNA typing convincingly excluded these accused men from paternity.

Blood Group Antigens↗

Role of septal vasopressin innervation in paternal behavior in prairie voles (Microtus ochrogaster).

After being paired with females, male prairie voles show major changes in their social behaviors among which is an increase in paternal responsiveness. These changes are accompanied by fluctuations in the density of the [Arg8]vasopressin-immunoreactive (AVP-ir) fibers in the lateral septum, suggesting that septal AVP might be involved in these changes. To explore a possible involvement of septal AVP in paternal responsiveness, we tested whether injections of saline, AVP, or the V1a receptor antagonist [1-(beta-mercapto-beta, beta-cyclopentamethylenepropionic acid),2-(O-methyltyrosine]AVP [d(CH2)5Tyr(Me)AVP] into the lateral septum influenced the four most prominent paternal activities displayed by male prairie voles; grooming, crouching over, contacting, and retrieving pups. In a first experiment, sexually inexperienced males received a single injection of AVP, saline, or d(CH2)5Tyr(Me)AVP in the lateral septum, after which their paternal responsiveness was recorded during a 10-min period. AVP-injected animals spent more time contacting and crouching over pups, while d(CH2)5Tyr(Me)AVP-injected animals spent less time grooming pups than saline-injected animals. In a follow-up study, one group of animals received an injection of AVP preceded by an injection of saline or d(CH2)5Tyr(Me)-AVP into the lateral septum. A second group of animals received an injection of saline preceded by an injection of saline or d(CH2)5Tyr(Me)AVP into the lateral septum. In both groups, animals spent less time grooming, crouching over, and contacting pups if they had first been injected with d(CH2)5Tyr(Me)AVP. Control experiments suggested that the effects of AVP on paternal responsiveness were dose- and site-specific. These data suggest that septal AVP enhances paternal responsiveness by a V1a receptor-mediated mechanism.

Animals↗

Advanced paternal age and risk of fetal death: a cohort study.

A possible detrimental paternal age effect on offspring health due to mutations of paternal origin should be reflected in an association between paternal age and fetal loss. The authors used data from a prospective study of 23,821 pregnant women recruited consecutively to the Danish National Birth Cohort from 1997 to 1999 to assess the association between paternal age and fetal death. Fathers of the pregnancies were identified by record linkage to population registers. The paternal age-related risks of fetal death and its components, early and late fetal loss, were estimated using survival analysis. Pregnancies fathered by a man aged 50 or more years (n = 124) had almost twice the risk of ending in a fetal loss compared with pregnancies with younger fathers (hazard ratio = 1.88, 95% confidence interval: 0.93, 3.82), after adjustment for maternal age, reproductive history, and maternal lifestyle during pregnancy. Various approaches to adjustment for potential residual confounding of the relation by maternal age did not affect the relative risk estimates. The paternal age-related risk of late fetal death was higher than the risk of early fetal death and started to increase from the age of 45 years. It should, however, be interpreted cautiously because of the restricted number of fetal deaths.

Abortion, Spontaneous↗